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补充乙醛酸可改善结肠炎相关结肠癌的进展。

Glyoxylate supplementation ameliorates colitis associated colon cancer progression.

机构信息

Department of Signal Transduction & Biogenic Amine, Chittaranjan National Cancer Institute, Kolkata, India.

Department of Biotechnology, Brainware University, Kolkata, India.

出版信息

J Cell Physiol. 2024 Nov;239(11):e31394. doi: 10.1002/jcp.31394. Epub 2024 Sep 5.

Abstract

Colon cancer is on the rise in younger adults. Despite multimodal treatment strategies, clinical outcomes in advanced stage colon cancer patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Overwhelming evidence supporting the small-molecule metabolites derived from breakdown of food or microbial sources confer an extensive array of host benefits, including chemo-preventive role in colon cancer. Our previous study indicated that the introduction of glyoxylate (Glx), an intermediate product of microbial or plant metabolism, exerts a cytotoxic effect in colon cancer cells. This study was designed to evaluate the effects of Glx on colon cancer with molecular insights. For this, we established an AOM/DSS-induced colitis associated colon cancer model in mice. Supplementation of Glx in vivo reduced colitis associated tumor growth and altered the metabolic characteristics of tumor tissue in mice without initiating any severe liver or renal toxicity. More specifically, intake of glyoxylate accumulated glycine in the colon tissue by elevation of alanine-glyoxylate transferase (AGXT) activity. Glycine accumulation increased intracellular Ca concentration via glycine receptor activation and dysregulation of Ca homeostasis lead to induction of apoptosis that resulted in arresting tumor growth. Interestingly, elevation of AGXT activity or Glx related specific metabolic pathway provides better survival in colon cancer patients. Collectively, our exclusive findings support the exploration of Glx either as a preventive molecule or its inclusion in the treatment regimens for colon cancer.

摘要

结肠癌在年轻人中的发病率正在上升。尽管采用了多模式治疗策略,但晚期结肠癌患者的临床结局仍然不佳。由于化疗耐药性、毒性和负面副作用,新辅助/辅助化疗的疗效有限。大量证据支持源自食物或微生物来源分解的小分子代谢物为宿主带来广泛的益处,包括在结肠癌中的化学预防作用。我们之前的研究表明,引入乙醛酸(Glx),一种微生物或植物代谢的中间产物,对结肠癌细胞具有细胞毒性作用。这项研究旨在通过分子研究评估 Glx 对结肠癌的影响。为此,我们在小鼠中建立了 AOM/DSS 诱导的结肠炎相关结肠癌模型。Glx 的体内补充减少了结肠炎相关肿瘤的生长,并改变了小鼠肿瘤组织的代谢特征,而没有引发任何严重的肝或肾毒性。更具体地说,通过提高丙氨酸-乙醛酸转氨酶(AGXT)活性,摄入乙醛酸会在结肠组织中积累甘氨酸。甘氨酸积累通过甘氨酸受体激活增加细胞内 Ca 浓度,并且 Ca 稳态的失调导致细胞凋亡的诱导,从而导致肿瘤生长的停滞。有趣的是,AGXT 活性或与 Glx 相关的特定代谢途径的升高为结肠癌患者提供了更好的生存。总之,我们的独家发现支持探索 Glx 作为预防分子或将其纳入结肠癌治疗方案的可能性。

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